Alternative titles; symbols
HGNC Approved Gene Symbol: EIF6
Cytogenetic location: 20q11.22 Genomic coordinates (GRCh38): 20:35,278,906-35,284,772 (from NCBI)
The integrin beta-4 subunit (ITGB4; 147557) is highly enriched in hemidesmosomes, specialized structures providing firm mechanical links between basal lamina and the intermediate filament cytoskeleton. A 303-amino acid segment of the ITGB4 cytoplasmic domain that encompasses the first 2 N-terminal fibronectin type III (FNIII) domains and their interconnecting sequence is necessary for mediating ITGB4 signaling events and incorporation into hemidesmosomes. Using a yeast 2-hybrid system to identify polypeptides that interact with this functional region of the ITGB4 cytodomain, Biffo et al. (1997) isolated human epithelial cell cDNAs encoding ITGB4-binding protein (ITGB4BP), which they called p27BBP. Southern blot analysis showed that the human genome contains a single copy of the ITGB4BP gene. Northern blot analysis and in situ hybridization detected Itgb4bp mRNA in all mouse tissues examined, with the highest levels mainly in proliferating epithelia and in epithelial tissues containing Itgb4. The predicted human ITGB4BP protein has 245 amino acids and lacks a signal sequence. Western blot analysis using antibodies against ITGB4BP detected a 27-kD protein in epithelial cell lysates, which is in agreement with the calculated molecular mass of ITGB4BP. Both in yeast and in vitro, ITGB4BP specifically bound to the first 2 FNIII domains of ITGB4. ITGB4BP is an insoluble protein that is present in the nucleus and cytoplasm. It is associated with the intermediate filament pool and is localized at the submembrane level in close apposition with ITGB4. The authors suggested that ITGB4BP links ITGB4 to the intermediate filament cytoskeleton.
Eukaryotic translation initiation factor-6 (EIF6) binds to the 60S ribosomal subunit and prevents its association with the 40S ribosomal subunit. Using antibodies against purified rabbit EIF6 protein to immunoscreen a HeLa cell cDNA expression library, Si et al. (1997) isolated a cDNA encoding EIF6. Northern blot analysis detected an approximately 1.1-kb transcript in all human tissues examined.
Ceci et al. (2003) demonstrated that the ribosomal 60S subunit is activated by release of EIF6. In the cytoplasm, EIF6 is bound to free 60S but not to 80S subunits. Furthermore, EIF6 interacts in the cytoplasm with RACK1 (176981), a receptor for activated protein kinase C (PKC; see 176960). RACK1 is a major component of translating ribosomes, which harbor significant amounts of PKC. Loading 60S subunits with EIF6 caused a dose-dependent translational block and impairment of 80S formation, which were reversed by expression of RACK1 and stimulation of PKC in vivo and in vitro. PKC stimulation led to EIF6 phosphorylation, and mutation of a serine residue in the carboxy terminus of EIF6 impaired RACK1/PKC-mediated translational rescue. Ceci et al. (2003) proposed that EIF6 release regulates subunit joining, and that RACK1 provides a physical and functional link between PKC signaling and ribosome activation.
To elucidate how microRNAs mediate their repressive effects, Chendrimada et al. (2007) performed biochemical and functional assays to identify new factors in the microRNA pathway. Chendrimada et al. (2007) showed that human RISC (RNA-induced silencing complex) associated with a multiprotein complex containing MOV10 (610742), the homolog of Drosophila translational repressor Armitage, and proteins of the 60S ribosome subunit. Notably, this complex contains the antiassociation factor EIF6, a ribosome inhibitory protein known to prevent productive assembly of the 80S ribosome. Depletion of EIF6 in human cells specifically abrogated miRNA-mediated regulation of target protein and mRNA levels. Similarly, depletion of EIF6 in C. elegans diminished Lin4 microRNA-mediated repression of the endogenous Lin14 and Lin28 (611043) target protein and mRNA levels. Chendrimada et al. (2007) concluded that their results uncovered an evolutionarily conserved function of the ribosome antiassociation factor EIF6 in microRNA-mediated posttranscriptional silencing.
Gandin et al. (2008) demonstrated that mammalian eIF6 is required for efficient initiation of translation in vivo. Eif6-null mouse embryos were lethal at preimplantation. Heterozygous mice had 50% reduction of eIF6 levels in all tissues, and showed reduced mass of hepatic and adipose tissues due to a lower number of cells and to impaired G1/S cell cycle progression. eIF6 heterozygous cells retained sufficient nucleolar eIF6 and normal ribosome biogenesis. The liver of eIF6 heterozygous mice displayed an increase of 80S in polysomal profiles, indicating a defect in initiation of translation. Consistently, isolated hepatocytes had impaired insulin-stimulated translation. Heterozygous mouse embryonic fibroblasts recapitulated the organism phenotype and had normal ribosome biogenesis, reduced insulin-stimulated translation, and delayed G1/S phase progression. Furthermore, eIf6 heterozygous cells were resistant to oncogene-induced transformation. Thus, Gandin et al. (2008) concluded that eIF6 is the first eIF associated with the large 60S subunit that regulates translation in response to extracellular signals.
De Marco et al. (2017) noted that Eif6 overexpression delays Xenopus eye development. They found that Eif6 interacted with Igf1r (147370) and inhibited the PI3K pathway (see 171833) in the Xenopus Eif6 overexpression phenotype. Delayed eye morphogenesis following Eif6 overexpression could be reversed by expression of Gipc2 (619089), an Igf1r interactor, and Gipc2 downregulation also caused delayed eye morphogenesis in Xenopus. Eif6 interacted with Gipc2 and modulated its expression in a dose-dependent manner to regulate morphogenesis of Xenopus eye. The PDZ domain of Gipc2 mediated interaction with Eif6 and was required for Gipc2 function.
By fluorescence in situ hybridization, Sanvito et al. (1998) mapped the ITGB4BP gene to 20q11.2.
Biffo, S., Sanvito, F., Costa, S., Preve, L., Pignatelli, R., Spinardi, L., Marchisio, P. C. Isolation of a novel beta-4 integrin-binding protein (p27BBP) highly expressed in epithelial cells. J. Biol. Chem. 272: 30314-30321, 1997. [PubMed: 9374518] [Full Text: https://doi.org/10.1074/jbc.272.48.30314]
Ceci, M., Gaviraghi, C., Gorrini, C., Sala, L. A., Offenhauser, N., Marchisio, P. C., Biffo, S. Release of eIF6 (p27-BBP) from the 60S subunit allows 80S ribosome assembly. Nature 426: 579-584, 2003. [PubMed: 14654845] [Full Text: https://doi.org/10.1038/nature02160]
Chendrimada, T. P., Finn, K. J., Ji, X., Baillat, D., Gregory, R. I., Liebhaber, S. A., Pasquinelli, A. E., Shiekhattar, R. MicroRNA silencing through RISC recruitment of elF6. Nature 447: 823-828, 2007. [PubMed: 17507929] [Full Text: https://doi.org/10.1038/nature05841]
De Marco, N., Tussellino, M., Carotenuto, R., Ronca, R., Rizzolio, S., Biffo, S., Campanella, C. Eukaryotic initiation factor eIF6 modulates the expression of Kermit 2/XGIPC in IGF-regulated eye development. Dev. Biol. 427: 148-154, 2017. [PubMed: 28472630] [Full Text: https://doi.org/10.1016/j.ydbio.2017.04.017]
Gandin, V., Miluzio, A., Barbieri, A. M., Beugnet, A., Kiyokawa, H., Marchisio, P. C., Biffo, S. Eukaryotic initiation factor 6 is rate-limiting in translation, growth and transformation. Nature 455: 684-688, 2008. [PubMed: 18784653] [Full Text: https://doi.org/10.1038/nature07267]
Sanvito, F., Arrigo, G., Zuffardi, O., Agnelli, M., Marchisio, P. C., Biffo, S. Localization of p27 beta-4 binding protein gene (ITGB4BP) to human chromosome region 20q11.2. Genomics 52: 111-112, 1998. [PubMed: 10348637]
Si, K., Chaudhuri, J., Chevesich, J., Maitra, U. Molecular cloning and functional expression of a human cDNA encoding translation initiation factor 6. Proc. Nat. Acad. Sci. 94: 14285-14290, 1997. [PubMed: 9405604] [Full Text: https://doi.org/10.1073/pnas.94.26.14285]